Recently, nanoparticles have played an increasingly significant role in diverse fields such as microelectronics, multiphase catalysis, sensing and therapeutics. (Nanoparticles: From Theory to Application; Schmid, Ed.; Wiley-VCH: Essen, 2004; Zhang, et al. Self-Assembled Nanostructures; Nanostructure Science and Technology Series; Springer: 2002; Nanoparticles: Building Blocks for Nanotechnology; Rotello, Ed.; Springer: 2003; Daniel, et al. 2004 Chem. Rev. 104, 293.) The ability to encapsulate and release guest molecules within the nanoparticle interior is required for applications such as sensing and therapeutics. For many applications, facile modulation of the nanoparticle surface is also important in order to obtain appropriate interfacial properties.
Amphiphilic molecules readily self-assemble into nanoassemblies, such as micelles and liposomes, which can encapsulate guest molecules within their interior spaces. (Harada, et al. 2006 Progress in Poly. Sci. 31, 949-982; O'Reilly, et al. 2006 Chem. Soc. Rev. 35, 1068-1083; Zhu, et al. 2012J. Mat. Chem. 22, 7667-7671; Owen, et al. 2012 Nano Today 7, 53-65; Sawant, et al. 2010 Soft Matter 6, 4026-4044; Micheli, et al. 2012 Recent Patents on CNS Drug Discovery 7, 71-86.)
A major challenge remains in developing polymeric nanogels wherein the backbones are fully degradable. In particular, methodologies are highly desired that allow significant control over the degradation of polymer backbones to small molecules that are generally regarded as safe (GRAS). This challenge is magnified due to the need to maintain a hydrophilic-lipophilic balance that is necessary for retention of the fidelity of the assembly while allowing efficient surface functionalization.
With regard to the development of drug delivery systems, significant attention has been paid to cancer therapy because of the severity and often-fatal nature of the disease. (Siegel, et al. 2014 CA-Cancer J. Clin. 64, 9-29.) Nanocarriers have emerged as a superior class of drug delivery system as they can exploit the leaky vasculature of tumor tissues for selective uptake. (Danhier, et al. 2010 J. Controlled Release. 148, 135-146; Maeda, et al. 2000 J. Controlled Release. 65, 271-284; Matsumura, et al. 1986 Cancer Res. 46, 6387-6392; Davis, et al. 2008 Nat. Rev. Drug Discov. 7, 771-782; Baban, et al. 1998 Adv. Drug Deliv. Rev. 34, 109-119; Duncan 2003 Nat. Rev. Drug Discov. 2, 347-360; Gillies, et al. 2005 Drug Discovery Today 10, 35-43; Peer, et al. 2007 Nat. Nanotechnol. 2, 751-760; Haag 2004 Angew. Chem. Int. Ed. 43, 278-282; Allen, et al. 2004 Scienc. 303, 1818-1822.)
Amongst the nanocarriers that are being developed for this purpose, polymeric micelles have attracted particular attention as these nanoassemblies can noncovalently encapsulate the hydrophobic drug molecules in aqueous conditions. (Kale, et al. 2009 Langmuir 25, 9660-9670; Koo, et al. 2005 Nanomedicine: NBM 1, 193-212; Liu, et al. 2009 Macromolecules 42, 3-13; Kataoka, et al. 2001 Adv. Drug Delivery Rev. 47, 113-131; Savic, et al. 2003 Science 300, 615-618; Torchilin 2001 J. Controlled Release 73, 137-172; Yin, et al. 2008 J. Controlled Release 131, 2-4; Kwon, et al. 1995 Adv. Drug Delivery Rev. 16, 295-309; Li, et al. 2014 Chem. Commun. 50, 13417-13432; Jeong, et al. 1997 Nature 388, 860-862; Kwon, et al. 1996 Adv. Drug Delivery Rev. 21, 107-116; Gref, et al. 1994 Science 263, 1600-1603.) Although polymer micelles show great promise in many cases, these assemblies face a general conundrum with respect to drug loading and encapsulation stability.
For high encapsulation stability, it is necessary that the hydrophobic part of the micellar assembly is glassy so as to keep the guest molecules from leaking into the bulk. On the other hand, if the interior of the assembly is glassy, loading the drug molecules become an issue. The successful utility of polymer micelles in the drug delivery area has demonstrated that ‘sweet spots’ can indeed be identified to develop useful nanocarriers. A complementary approach that can offer a viable solution to this issue involves chemically crosslinked polymeric assemblies, where the loading can occur when the assemblies are rather lose and the encapsulation stability is achieved due to the crosslinking-induced incarceration of the drug molecules. (Ryu, et al. 2010 J. Am. Chem. Soc. 132, 8246-8247; Oh, et al. 2008 Prog. Polym. Sci. 33, 448-477; Molla, et al. 2014 Biomacromolecules 15, 4046-4053; Rossler, et al. 2012 Adv. Drug Delivery Rev. 64, 270-279; Peppas, et al. 2000 Eur. J Pharm. Biopharm. 50, 27-46.) Such a crosslinking strategy also offers the opportunity to program the assemblies to uncrosslink and release its contents only in the presence of a specific stimulus. (Ganta, et al. 2008 J. Controlled Release 126, 187-204; Shenoy, et al. 2005 Pharm. Res. 22, 2107-2114; Shenoy, et al. 2005 Mol. Pharmacol. 2, 357-366; Kommareddy, et al. 2005 Bioconjug. Chem. 16, 1423-1432; Meyer, et al. 2001 J. Control. Release. 74, 213-224; Saito, et al. 2003 Adv. Drug Deliv. 55, 199-215; Arrueboa, et al. 2007 Nano Today 2, 22-32; Ito, et al. 2005 J. Biosci. Bioeng. 100, 1-11; Rapoport, et al. 2002 Drug Deliv. Syst. Sci. 2, 37-46; Gao, et al. 2005 J. Control. Release 102, 203-221; Rapoport 2007 Prog. Polym. Sci. 32, 962-990.)
As safety of the drug carriers is of utmost importance, it is critical that a carrier is biocompatible. (Matsumura, et al. 2009 Cancer Sci. 100, 572-579; Kim, et al. 2004 Clin. Cancer Res. 10, 3708; Matsumura, et al. 2004 Br. J. Cancer. 91, 1775-1781; Hamaguchi, et al. 2010 Clin. Cancer Res. 16, 5058-5066; Katti, et al. 2002 Adv. Drug Delivery Rev. 54, 933-961; Ulery, et al. 2011 J. Polym. Sci., Part B: Polym. Phys. 49, 832-864; Friess Eur. 1998 J. Pharm. Biopharm. 45, 113-136; Middleton, et al. 2000 Biomaterials 21, 2335-2346; Deng, et al. 2012 Nano Today 7, 467-480.)
Thus, there is a continued need for novel approach to develop biocompatible scaffolds is to design the components of the assembly such that they are biodegradable and that the degradation products are non-toxic.